Updated on 2024/04/19

写真a

 
Kuwabara Yoshimitsu
 
Affiliation
Nippon Medical School Hospital, Department of Obstetrics and Gynecology, Associate Professor
Title
Associate Professor
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Degree

  • 博士(医学)

Research Interests

  • Reproductive endocrinology

  • Recurrent pregnancy loss

  • Preterm birth

  • Perinatology

  • Reproductive medicine

Research Areas

  • Life Science / Obstetrics and gynecology

Education

  • Nippon Medical School   Graduate School

    1999 - 2003

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  • Nippon Medical School   Medical School

    1991 - 1997

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Research History

  • Nippon Medical School   Associate Professor

    2013

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  • Nippon Medical School   Senior Assistant Professor

    2012

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  • Nippon Medical School   Senior Assistant Professor

    2010

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  • 日本私立学校振興・共済事業団 東京臨海病院   産婦人科   医長

    2008

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  • Nippon Medical School

    2007

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  • スタンフォード大学   Department of obstetrics and Gynecology   Postdoctral fellow

    2004 - 2006

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  • Nippon Medical School

    2003

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  • 葛飾赤十字産院   産婦人科   医師

    1999

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  • Nippon Medical School

    1997

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Papers

  • Guideline for gynecological practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2023 edition. International journal

    Eiji Nishio, Ken Ishitani, Takahide Arimoto, Toshio Igarashi, Tetsuya Ishikawa, Akira Iwase, Mariko Ogawa, Nobuaki Ozawa, Hiroaki Kajiyama, Kaoru Kawasaki, Risa Kudo, Jun Kumakiri, Hiroko Komura, Kan Komai, Seiya Sato, Koichi Shinohara, Toshifumi Takahashi, Kyoko Tanaka, Kyoko Tanebe, Masashi Deguchi, Akiko Tozawa-Ono, Akitoshi Nakashima, Mikiya Nakatsuka, Satoshi Hayakawa, Tetsuya Hirata, Rie Fukuhara, Yasuka Miyakuni, Hiroaki Miyazaki, Tohru Morisada, Yoshimitsu Kuwabara, Masataka Takenaka, Makio Shozu, Mayumi Sugiura-Ogasawara, Tsugio Maeda, Yoshihito Yokoyama, Takuma Fujii

    The journal of obstetrics and gynaecology research   2024.4

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    Language:English   Publishing type:Research paper (scientific journal)  

    Twelve years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 5th Revised Edition was published in 2023. The 2023 Guidelines includes 5 additional clinical questions (CQs), which brings the total to 103 CQ (12 on infectious disease, 30 on oncology and benign tumors, 29 on endocrinology and infertility and 32 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

    DOI: 10.1111/jog.15950

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  • Assisted reproductive technology in Japan: A summary report for 2021 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology.

    Yukiko Katagiri, Seung Chik Jwa, Akira Kuwahara, Takeshi Iwasa, Masanori On, Keiichi Kato, Hiroshi Kishi, Yoshimitsu Kuwabara, Fuminori Taniguchi, Miyuki Harada, Akira Iwase, Yutaka Osuga

    Reproductive medicine and biology   23 ( 1 )   e12552   2024

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    PURPOSE: The Japan Society of Obstetrics and Gynecology (JSOG) registry gathers comprehensive data from registered assisted reproductive technology (ART) facilities in Japan. Herein, we report 2021 ART cycle characteristics and outcomes. METHODS: Descriptive statistics were used to summarize and analyze 2021 data. RESULTS: In 2021, 625 ART facilities participated in the registry; 27 facilities did not conduct ART cycles and 598 registered treatment cycles. In total, 498 140 cycles were registered, and there were 69 797 neonates (increases of 10.7% and 15.5%, respectively, from the previous year). The number of freeze-all in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles decreased in 2021; the number of neonates born was 2268 for IVF-embryo transfer (ET) cycles and 2850 for ICSI cycles. Frozen-thawed ET (FET) cycles increased markedly from 2020 (11.2% increase). In 2021, 239 428 FET cycles were conducted, resulting in 87 174 pregnancies and 64 679 neonates. For fresh transfers, the total single ET, singleton pregnancy rate, and singleton live birth rates were 82.7%, 97.0%, and 97.3%; for FET, these rates were 84.9%, 96.9%, and 97.1%. CONCLUSIONS: The 2021 Japanese ART registry analysis showed marked increases in both total treatment cycles and live births from the previous year.

    DOI: 10.1002/rmb2.12552

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  • Superfertility and subfertility in patients with recurrent pregnancy loss: A comparative analysis of clinical characteristics and etiology based on differences in fertile ability. International journal

    Sayuri Kasano, Yoshimitsu Kuwabara, Shingo Ogawa, Ryoko Yokote, Mirei Yonezawa, Nozomi Ouchi, Tomoko Ichikawa, Shunji Suzuki, Toshiyuki Takeshita

    Journal of reproductive immunology   159   104129 - 104129   2023.9

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    This study aimed to elucidate the etiologies of and risk factors for recurrent pregnancy loss (RPL) according to fertile ability, focusing on the differences between superfertile and subfertile patients. This retrospective observational study included 828 women with RPL between July 2017 and February 2020. Patients were divided into three groups based on time to pregnancy (TTP): superfertile (SUP) (TTP ≤3 months for all previous pregnancies), subfertile (SUB) (previous TTP ≥12 months and use of assisted reproductive technology [ART]), and Normal (N) (TTP >3 or <12 months without ART). All patients were assessed for uterine anatomy, antiphospholipid antibodies (APAs), thyroid function, and thrombophilia. Of the 828 patients, 22%, 44%, and 34% were assigned to the SUP, SUB, and N groups, respectively. The mean ages were 33.9, 38.2, and 35.9 years in the SUP, SUB, and N groups, respectively, revealing a significant difference (P < 0.001). The anti-CL β2GPI antibody positivity rate was significantly higher in the SUP group (4.6%) than in the N group (0.8%; P = 0.016). The prevalence of APA positivity was lowest in the N group. Overall, the clinical characteristics and etiologies of RPL associated with superfertility and subfertility were strikingly similar, with comparable positivity rates after adjusting for maternal age. Further investigation including chromosomal analysis of products of conception is needed to elucidate the clinical impact of differences in fertility on patients with RPL.

    DOI: 10.1016/j.jri.2023.104129

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  • Characteristic impairment of progesterone response in cultured cervical fibroblasts obtained from patients with refractory cervical insufficiency International journal

    Yosuke Sugita, Yoshimitsu Kuwabara, Akira Katayama, Shigeru Matsuda, Ichiro Manabe, Shunji Suzuki, Yumiko Oishi

    Scientific Reports   13 ( 1 )   11709 - 11709   2023.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    Abstract

    Preterm birth (PTB) is the leading cause of neonatal mortality, and reducing the PTB rate is one of the most critical issues in perinatal medicine. Cervical insufficiency (CI), a major cause of PTB, is characterised by premature cervical ripening in the second trimester, followed by recurrent pregnancy loss. Although multiple clinical trials have suggested that progesterone inhibits cervical ripening, no studies have focused on progesterone-induced molecular signalling in CI. Here, we established a primary culture system for human uterine cervical fibroblasts using a sample of patients with refractory innate CI who underwent transabdominal cervical cerclage and patients with low Bishop scores who underwent elective caesarean section as controls. RNA sequencing showed that the progesterone response observed in the control group was impaired in the CI group. This was consistent with the finding that progesterone receptor expression was markedly downregulated in CI. Furthermore, the inhibitory effect of progesterone on lipopolysaccharide-induced inflammatory stimuli was also impaired in CI. These results suggest that abnormal cervical ripening in CI is caused by the downregulation of progesterone signalling at the receptor level, and provide a novel insight into the molecular mechanism of PTB.

    DOI: 10.1038/s41598-023-37732-7

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    Other Link: https://www.nature.com/articles/s41598-023-37732-7

  • Risk factors for persistent positive anticardiolipin antibodies in women with recurrent pregnancy loss

    R. Yokote, Y. Kuwabara, S. Kasano, M. Yonezawa, N. Ouchi, T. Ichikawa, S. Suzuki, T. Takeshita

    Journal of Reproductive Immunology   156   103920 - 103920   2023.3

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    Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.jri.2023.103920

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  • Carcinosarcoma of the uterus, derived from subserous cystic adenomyosis, presenting as an acute abdomen: A case report and review of the literature. International journal

    Kaoru Hashizume, Masafumi Toyoshima, Tatsunori Shiraishi, Yuta Ueno, Akihito Yamamoto, Rieko Kawase, Yoshimitsu Kuwabara, Takashi Sakatani, Shunji Suzuk

    Gynecologic oncology reports   45   101139 - 101139   2023.2

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    When a woman presents with an acute abdomen with cystic lesions in the abdominal cavity, the differential diagnosis includes torsion or rupture of an ovarian tumor. We report our experience with a 54-year-old nulliparous woman who underwent emergency surgery for a suspected ruptured ovarian tumor. Intraoperative examination revealed disruption of a cystic tumor that had developed externally from the fundus of the uterus. The patient, who was taking aspirin because of a history of medullary infarction, reported lower abdominal discomfort for several days. When she sought care, she was referred to the gynecology department where transvaginal ultrasonography and contrast-enhanced computed tomography showed a poorly toned mass with a maximum diameter of 20 cm posterior to the uterus. She also had a large amount of ascites reaching around the liver and the spleen. She underwent an emergency laparotomy for a presumed diagnosis of acute abdomen caused by a ruptured ovarian tumor with intra-abdominal bleeding. Intraoperative examination revealed normal adnexae bilaterally, but there was a cystic tumor in the pouch of Douglas that was strongly adherent to the surrounding intestines. This mass was connected to the posterior uterus by a stalk and appeared to be continuous with the uterine tissue. The postoperative pathological diagnosis was carcinosarcoma derived from subserous cystic adenomyosis. This is the first case report of carcinosarcoma developing from subserous cystic adenomyosis in the English literature as far as we know.

    DOI: 10.1016/j.gore.2023.101139

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  • Assisted reproductive technology in Japan: A summary report for 2020 by the ethics Committee of the Japan Society of obstetrics and gynecology.

    Yukiko Katagiri, Seung Chik Jwa, Akira Kuwahara, Takeshi Iwasa, Masanori Ono, Keiichi Kato, Hiroshi Kishi, Yoshimitsu Kuwabara, Miyuki Harada, Toshio Hamatani, Yutaka Osuga

    Reproductive medicine and biology   22 ( 1 )   e12494   2023

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    PURPOSE: Since 1986, the Japan Society of Obstetrics and Gynecology assisted reproductive technology (ART) registry system has collected data on national ART use and outcomes trends in Japan. Herein, we describe the characteristics and outcomes of ART cycles registered during 2020 and compare the results with those from 2019. METHODS AND RESULTS: In 2020, 621 ART facilities participated in the registration. The total number of registered cycles was 449 900, and there were 60 381 live births, which decreased from the previous year (1.79% and 0.36% decrease, respectively). The number of freeze-all in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles increased in 2020, and the number of neonates born was 2282 for IVF-embryo transfer (ET) cycles and 2596 for ICSI cycles, which had decreased from the previous year. Frozen-thawed ET (FET) cycles had slightly increased from 2019 (0.04%). In 2020, 215 285 FET cycles were conducted, resulting in 76 196 pregnancies and 55 503 neonates. Single ET was performed in 81.6% of fresh transfers and 85.1% of frozen-thawed cycles, respectively, resulting in over 97% singleton pregnancies/livebirths rates. CONCLUSION: Despite the COVID-19 pandemic during 2020, the overall number of ART cycles and neonates born demonstrated only a slight decrease in 2020 compared with 2019.

    DOI: 10.1002/rmb2.12494

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  • Preeclampsia in a pregnant woman with severe aplastic anemia: A case report. International journal

    Ikuno Kawabata, Ryoko Yokote, Sayuri Kasano, Jun Ogawa, Masahiko Kato, Tomoko Ichikawa, Mirei Yonezawa, Yoshimitsu Kuwabara, Hiroki Yamaguchi, Shunji Suzuki

    Clinical case reports   10 ( 12 )   e6789   2022.12

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    A pregnant woman with severe aplastic anemia was managed using biweekly red blood cell transfusion and oral eltrombopag olamine administration during pregnancy. She was diagnosed with preeclampsia at 35 weeks of gestation. The severity of aplastic anemia is very important for predicting the course of pregnancy.

    DOI: 10.1002/ccr3.6789

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  • Maternal cell contamination in embryonic chromosome analysis of missed abortions. International journal

    Nozomi Ouchi, Toshiyuki Takeshita, Sayuri Kasano, Ryoko Yokote, Mirei Yonezawa, Ryuhei Kurashina, Tomoko Ichikawa, Ikuno Kawabata, Yoshimitsu Kuwabara, Shunji Suzuki

    The journal of obstetrics and gynaecology research   48 ( 7 )   1641 - 1647   2022.4

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    AIM: The fetal sample used for embryonic chromosome analysis is often contaminated with maternal cells, making it difficult to evaluate the fetal chromosomes. We examined on the rate of maternal cell contamination and its relationship with maternal information in the embryonic chromosome analysis of missed abortions using the Giemsabanding method. METHODS: Chromosome analysis was performed in 200 cases of delayed miscarriages in first trimester between July 1, 2000 and May 31, 2019. Chorionic villi were collected and were analyzed using the Giemsa banding method. Among the 20 cells for which chromosomal examination was performed, cells wherein 46,XX chromosomes were found together with normal male karyotype or abnormal chromosomes were defined as maternal cell contamination. RESULTS: Of the 200 cases analyzed, 136 had abnormal chromosomes. The normal female karyotype (n = 52) was four times more prevalent than the normal male karyotype (n = 12). Maternal cell contamination was seen in 15.4% of the abnormal chromosome cases and 8.3% of the normal male karyotype cases. There was no significant difference in the gestational age between the contaminated and noncontaminated groups at the time of miscarriage diagnosis. However, miscarriage before fetal heartbeat confirmation was significantly associated with higher maternal cell contamination. CONCLUSION: We found maternal cell contamination in 15% of all the cases. Moreover, in many cases of the normal female karyotype, it was suspected that only maternal chromosomes were cultured. When performing embryonic chromosome analysis in recurrent miscarriages, we should pay attention to maternal cell contamination and interpret the results accordingly.

    DOI: 10.1111/jog.15249

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  • Effects of Thrombophilia and Antithrombotic Therapy on Embryonic Chromosomal Aberration Rates in Patients with Recurrent Pregnancy Loss.

    Nozomi Ouchi, Toshiyuki Takeshita, Sayuri Kasano, Ryoko Yokote, Mirei Yonezawa, Ryuhei Kurashina, Tomoko Ichikawa, Ikuno Kawabata, Yoshimitsu Kuwabara

    Journal of Nippon Medical School = Nippon Ika Daigaku zasshi   89 ( 1 )   40 - 46   2022.3

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    BACKGROUND: Miscarriage occurs in 10-15% of pregnancies and recurrent pregnancy loss (RPL) occurs in 1% of couples hoping for a child. Various risk factors, such as thrombophilia, uterine malformation, and embryonic chromosomal aberration cause RPL. We hypothesized that antithrombotic therapy for RPL patients with thrombophilia would reduce miscarriage due to thrombophilia, which would reduce the total miscarriages and result in a relative increase in miscarriage due to embryonic chromosomal aberrations. In this study, we investigated the incidence of chromosomal aberrations in products of conception in RPL patients with and without antithrombotic therapy. METHODS: We performed a single-center, retrospective review of cases diagnosed as miscarriage with embryo chromosome analysis between July 1, 2000, and May 31, 2019. Rates of chromosomal aberration were compared between RPL patients with and without thrombophilia or antithrombotic therapy. RESULTS: One hundred and-ninety RPL cases were analyzed. The average age was 37.4 ± 4.3 years, and the average number of previous pregnancy losses was 2.2 ± 1.1. The overall chromosomal aberration rate was 67.4% (128/190). There was no difference in the chromosomal aberration rate between the factors for RPL, with or without thrombophilia, and antithrombotic therapy. Only advancing maternal age had significant correlation to increased embryo chromosomal aberration rates. CONCLUSIONS: With or without antithrombotic therapy, miscarriage was caused by embryonic chromosome abnormalities at a certain rate. Antithrombotic therapy in RPL patients with thrombophilia may reduce abortions due to thrombophilia, which may also normalize the rate of embryonic chromosome aberrations in the subsequent miscarriages.

    DOI: 10.1272/jnms.JNMS.2022_89-103

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  • Successful in vitro fertilization pregnancy and delivery in an infertile patient with ovotesticular disorder of sex development: a case report.

    Shigeru Matsuda, Yoshimitsu Kuwabara, Ryoko Kato, Kimihiko Nakao, Mirei Yonezawa, Shuichi Ono, Tomoko Ichikawa, Shigeo Akira, Toshiyuki Takeshita

    Journal of Nippon Medical School = Nippon Ika Daigaku zasshi   2022.1

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    A 29-year-old nulliparous woman was diagnosed with ovotesticular disorder of sex development (DSD) based on postoperative histopathological findings after undergoing unilateral gonadectomy at the age of 6 years; later (age of 8 years), she had also undergone vulvoplasty and vaginoplasty. Her karyotype was 46, XX. She had dyspareunia because of a narrow vagina, but had a normal uterus and left gonad.Spontaneous ovulation was confirmed, but sexual intercourse was impossible because of dyspareunia despite performing vaginal self-dilatation using a vaginal dilator. Artificial insemination was initiated; however, five cycles failed to yield a viable pregnancy. We decided to perform in vitro fertilization (IVF), which resulted in conception. To reduce her distress during IVF because of insufficient lumen expansion following vaginoplasty, we administered adequate intravenous anesthesia before oocyte collection. The patient delivered a healthy male infant weighing 2,558 g at 37 weeks of gestation via cesarean section, which was performed because of gestational hypertension. This is the eighth report of a viable neonate born from a patient with ovotesticular DSD following gonadectomy and the first such pregnancy achieved by IVF. Therefore, IVF seems to be an effective option for infertile patients with ovotesticular DSD. Additionally, self-management of the plastic vagina is important during the peri- and postoperative periods of early vaginoplasty to prevent dyspareunia.

    DOI: 10.1272/jnms.JNMS.2023_90-202

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  • Upregulated serum granulysin levels in women with antiphospholipid antibody‐associated recurrent miscarriage are downregulated by heparin treatment

    Tomoko Ichikawa, Yasuyuki Negishi, Sayuri Kasano, Ryoko Yokote, Mirei Yonezawa, Nozomi Ouchi, Yoshimitsu Kuwabara, Shunji Suzuki, Toshiyuki Takeshita

    Reproductive Medicine and Biology   21 ( 1 )   2022.1

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    Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1002/rmb2.12460

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    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/rmb2.12460

  • Assisted reproductive technology in Japan: A summary report for 2019 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology.

    Yukiko Katagiri, Seung Chik Jwa, Akira Kuwahara, Takeshi Iwasa, Masanori Ono, Keiichi Kato, Hiroshi Kishi, Yoshimitsu Kuwabara, Miyuki Harada, Toshio Hamatani, Yutaka Osuga

    Reproductive medicine and biology   21 ( 1 )   e12434   2022

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    PURPOSE: The Japan Society of Obstetrics and Gynecology records online annual cycle-based information for assisted reproductive technology (ART). This report presents the characteristics and treatment outcomes of ART cycles registered during 2019. METHODS: The Japanese ART registry includes cycle-specific information from 619 participating facilities, including treatment and pregnancy outcomes. Descriptive analyses were conducted for cycles registered during 2019. RESULTS: In 2019, 458 101 treatment cycles and 60 598 neonates were reported, both of which increased from 2018. The number of fresh cycles, including in vitro fertilization and intracytoplasmic sperm injection, decreased, while frozen-thawed embryo transfer (ET) cycles increased. The mean maternal age was 37.9 years (standard deviation ± 4.7). Of 239 348 oocyte retrievals, 123 690 (51.7%) involved freeze-all-embryos cycles; fresh ET was performed in 41 831 cycles (a decreasing trend since 2015). In 2019, there were 211 597 frozen-thawed ET cycles, resulting in 74 882 pregnancies and 54 168 neonates born. Single ET was performed in 82.6% of fresh transfers and 85.1% of frozen-thawed cycles, with singleton live birth rates of 97.3% for both. CONCLUSIONS: The number of fresh cycles decreased but frozen cycles increased in 2019. Single ET was performed in >80% of cases, and the proportion of babies born from frozen-thawed ET increased.

    DOI: 10.1002/rmb2.12434

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  • A report on the 73th Annual Congress of the Japan Society of Obstetrics and Gynecology International Workshop for Junior Fellows: Risk-reducing surgery for hereditary breast and ovarian cancer. International journal

    Takashi Hirayama, Yoshihide Inayama, Suguru Odajima, Akina Yamanaka, Masayuki Sekine, Yasuhisa Terao, Keiko Koide, Yoshimitsu Kuwabara, Hideaki Yahata, Nozomu Yanaihara, Satoru Nagase, Yoichi Kobayashi, Akihiko Sekizawa

    The journal of obstetrics and gynaecology research   47 ( 11 )   3761 - 3766   2021.11

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    At the 73rd Annual Congress of the Japan Society of Obstetrics and Gynecology, young doctors from Japan and South Korea made presentations on the present condition of risk-reducing surgery for hereditary breast and ovarian cancer (RRSO) in their respective country. RRSO was insured in Japan in April 2020, whereas in South Korea, it was insured 7 years earlier in 2013. In Japan, certification criteria have been set for facilities that perform RRSO, and the number of facilities is increasing, but regional disparities still exist in its distribution. The number of gBRCA1/2 testing facilities is larger, and the cost is more affordable in South Korea than in Japan. Additionally, South Korea provides genetic counseling to a wider range of relatives compared to Japan. In the future, as the indications for the gBRCA1/2 test have expanded as a companion diagnostic for the use of PARP inhibitors, it is expected that the number of candidates for the gBRCA1/2 mutation test and RRSO will increase in Japan. It is important to increase the number of BRCA tests while maintaining the quality of genetic counseling in order to provide adequate information on BRCA mutations and RRSO for patients to support their decision. For the development of hereditary breast and ovarian cancer (HBOC) medical care, it is necessary to publish a nationwide database in Japan and continue to analyze and discuss the data based on the results.

    DOI: 10.1111/jog.14952

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  • Plasma and follicular fluid osteopontin levels during ovarian cycle and their correlation with follicular fluid vascular endothelial growth factor levels. International journal

    Yoshimitsu Kuwabara, Shuichi Ono, Akira Katayama, Sachiko Kurihara, Yumiko Oishi, Toshiyuki Takeshita

    Scientific reports   11 ( 1 )   286 - 286   2021.1

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    Osteopontin (OPN) is a multifunctional secreted glycoprotein. We evaluated OPN concentrations in blood and follicular fluid (FF) during the ovarian cycle and their relationship with the production of vascular endothelial growth factor (VEGF), which is involved in the pathophysiology of ovarian hyperstimulation syndrome (OHSS). Twenty-two women undergoing in vitro fertilization (minimal stimulation protocol with clomiphene citrate) were enrolled. Samples were collected (a) on the third day of withdrawal bleeding, (b) 2 days before oocyte retrieval, and (c) on the day of oocyte retrieval. FF was collected during oocyte retrieval. The OPN concentration in each specimen and the VEGF concentration in FF was measured by enzyme-linked immunosorbent assays. Plasma OPN concentrations were (in ng/mL): (a) 416 ± 37.2, (b) 378 ± 35.8, and (c) 390 ± 40.0, with no significant differences between the groups. The OPN concentration in FF was 106 ± 13.4 ng/mL. A positive correlation was found between OPN concentrations in FF and plasma samples. A positive correlation was also found between plasma OPN and FF VEGF concentrations, irrespective of the blood-sampling period. Plasma OPN concentration is suggested to reflect the FF VEGF level at oocyte retrieval and maybe a novel clinical marker for predicting the risk for OHSS.

    DOI: 10.1038/s41598-020-79453-1

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  • Guideline for Gynecological Practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2020 edition. International journal

    Ryuji Kawaguchi, Koji Matsumoto, Tetsuya Ishikawa, Ken Ishitani, Ryugo Okagaki, Mariko Ogawa, Toshimichi Oki, Nobuaki Ozawa, Kaoru Kawasaki, Yoshimitsu Kuwabara, Kaori Koga, Yuichi Sato, Yasushi Takai, Kyoko Tanaka, Kyoko Tanebe, Masakazu Terauchi, Yukiharu Todo, Sayaka Nose-Ogura, Tsuneo Noda, Tsukasa Baba, Eriko Fujii, Takuma Fujii, Hiroaki Miyazaki, Osamu Yoshino, Kazuaki Yoshimura, Tsugio Maeda, Yoshiki Kudo, Hiroshi Kobayashi

    The journal of obstetrics and gynaecology research   47 ( 1 )   5 - 25   2021.1

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    Nine years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 4th Revised Edition was published in 2020. The 2020 Guidelines includes 4 additional clinical questions (CQ), which brings the total to 99 CQ (12 on infectious disease, 29 on oncology and benign tumors, 29 on endocrinology and infertility and 29 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

    DOI: 10.1111/jog.14487

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  • Assisted reproductive technology in Japan: A summary report for 2018 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology.

    Osamu Ishihara, Seung Chik Jwa, Akira Kuwahara, Yukiko Katagiri, Yoshimitsu Kuwabara, Toshio Hamatani, Miyuki Harada, Yutaka Osuga

    Reproductive medicine and biology   20 ( 1 )   3 - 12   2021.1

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    Purpose: Since 2007, the Japan Society of Obstetrics and Gynecology (JSOG) has collected cycle-based data for assisted reproductive technology (ART) in an online registry. Here, we present the characteristics and treatment outcomes of ART cycles registered during 2018. Methods: The Japanese ART registry consists of cycle-specific information for all ART treatment cycles implemented at 621 participating facilities. We conducted descriptive analyses for such cycles registered for 2018. Results: In total, 454 893 treatment cycles and 56 979 neonates were reported in 2018: both increased from 2017. The mean maternal age was 38.0 years (standard deviation ± 4.7). Of 247 402 oocyte retrievals, 118 378 (47.8%) involved freeze-all-embryos cycles; fresh embryo transfer (ET) was performed in 50 463 cycles: a decreasing trend since 2015. A total of 199 914 frozen-thawed ET cycles were reported, resulting in 69 357 pregnancies and 49 360 neonates born. Single ET (SET) was performed in 82.2% of fresh transfers and 83.4% of frozen-thawed cycles, with singleton pregnancy/live birth rates of 97.2%/97.2% and 97.0%/97.2%, respectively. Conclusions: Total ART cycles and subsequent live births increased in 2018. SET was performed in over 80% of cases, and the mode of ET has shifted continuously from using fresh embryos to frozen-thawed ones compared with previous years.

    DOI: 10.1002/rmb2.12358

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  • Influence of second stage of labor duration on umbilical artery lactate levels in uncomplicated multiparous women

    Ryuhei Kurashina, Yoshimitsu Kuwabara, Toshiyuki Takeshita, Shunji Suzuki

    HYPERTENSION RESEARCH IN PREGNANCY   9 ( 3 )   55 - 59   2021

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:JAPAN SOC STUDY HYPERTENSION PREGNANCY  

    Aim: We examined the relationship between second stage of labor duration and umbilical artery lactate levels in uncomplicated multiparous women.Methods: This was a retrospective study of 789 healthy multiparous women with no history of caesarean section and singleton pregnancy, who had a vaginal delivery after 37 weeks' gestation at our institutes between August 2015 and March 2017. As controls, 1,082 uncomplicated nulliparous women who gave birth during the same period were also examined.Results: The average umbilical artery lactate level increased with increasing second stage of labor duration (p < 0.05) in multiparous women. Multiparous women with a second stage of labor duration of 0-60 min had a significantly lower average lactate level compared to nulliparous women (p < 0.05), while those with a second stage of labor duration of 121-180 min had a significantly higher average lactate level compared to nulliparous women (p < 0.05).Conclusion: A prolonged second stage of labor duration was associated with increased umbilical artery lactate levels.

    DOI: 10.14390/jsshp.HRP2021-008

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  • Infertility treatment hinders the careers of working women in Japan. Reviewed International journal

    Tomoko Ichikawa, Ikuko Ota, Yoshimitsu Kuwabara, Ruriko Tsushima, Toshio Hamatani, Osamu Hiraike, Toshiyuki Takeshita, Yutaka Osuga, Shigeo Akira

    The journal of obstetrics and gynaecology research   46 ( 10 )   1940 - 1950   2020.10

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    AIM: Women undergoing infertility treatment often need to balance work and fertility treatment. Therefore, we evaluated the quality of life (QOL) and impact of infertility treatment on Japanese working women and their careers. METHODS: We conducted an online questionnaire at 18 clinics in Japan. Responses were collected from 835 women, 713 of whom were working. The participants were divided into three groups based on treatment stage. Data were collected using the FertiQoL and an original questionnaire created by the authors. The Mann-Whitney U test and a multinomial logistic analysis were used. RESULTS: Approximately 90% of the participants felt that treatment could hinder their work and 8% had quit their jobs. Low QOL was associated with sadness and despair due to infertility and mood disorders, disruptions to life and work, and the complicated medications and procedures involved in treatment. Social isolation and the effect of fertility treatment on daily life and work strongly hindered the careers of working women in the third stage of treatment (in vitro fertilization and intracytoplasmic sperm injection). Approximately 70% of the participants required support to subsidize treatment costs and sought shorter working hours and flextime systems. Only 55% informed their workplaces about the fertility treatment, but about 70% easily gained understanding by informing them. CONCLUSIONS: For many working women, infertility treatment posed barriers to their careers, which could explain the low QOL. Urgent introduction of a support system is necessary in Japan, and understanding and social acceptance of infertility appears to be important.

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  • Inappropriate activation of invariant natural killer T cells and antigen-presenting cells with the elevation of HMGB1 in preterm births without acute chorioamnionitis. Reviewed International journal

    Masahiko Kato, Yasuyuki Negishi, Yoshio Shima, Yoshimitsu Kuwabara, Rimpei Morita, Toshiyuki Takeshita

    American journal of reproductive immunology (New York, N.Y. : 1989)   85 ( 1 )   e13330   2020.8

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    PROBLEM: Acute chorioamnionitis (aCAM) associated with microbial infection is a primary cause of preterm birth (PB). However, recent studies have demonstrated that innate immunity and sterile inflammation are causes of PB in the absence of aCAM. Therefore, we analyzed immune cells in the decidua of early to moderate PB without aCAM. METHOD OF STUDY: Deciduas were obtained from patients with PB at a gestational age of 24+0 to 33+6  weeks without aCAM in pathological diagnosis. The patients were divided into two groups as follows: patients with labor and/or rupture of membrane (ROM) (no aCAM with labor and/or ROM: nCAM-w-LR), and patients without labor and/or ROM (no aCAM without labor and/or ROM: nCAM-w/o-LR). The immune cells and high mobility group box 1 (HMGB1) levels in the decidua were analyzed using flow cytometry. Co-culture of CD56+ cells with dendritic cells (DCs) and macrophages obtained from the decidua was also performed in the presence of HMGB1. RESULTS: The nCAM-w-LR group demonstrated an accumulation of iNKT cells, and increased expression of HMGB1, TLR4, receptors for advanced glycation end products, and CD1d on DCs and macrophages. HMGB1 facilitated the proliferation of iNKT cells co-cultured with DCs and macrophages, which was found to be inhibited by heparin. CONCLUSIONS: Inappropriate activation of innate immune cells and increased HMGB1 expression may represent parturition signs in human pregnancy. Therefore, control of these cells and HMGB1 antigenicity may be represent a potential therapeutic target for the prevention of PB.

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  • Significance of Anti-Phosphatidylethanolamine Antibodies in the Pathogenesis of Recurrent Pregnancy Loss. Reviewed International journal

    Mirei Yonezawa, Yoshimitsu Kuwabara, Shuichi Ono, Nozomi Ouchi, Tomoko Ichikawa, Toshiyuki Takeshita

    Reproductive sciences (Thousand Oaks, Calif.)   27 ( 10 )   1888 - 1893   2020.6

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    Anti-phosphatidylethanolamine antibody (aPE), an anti-phospholipid autoantibody (aPL), has been proposed as a factor in recurrent pregnancy loss (RPL). However, conflicting views exist on the pathogenicity of RPL, and aPE has not yet been included in the classification criteria for antiphospholipid syndrome (APS). Here, we aimed to determine the clinical importance of examining aPE. aPE (IgG, IgM) was measured in 1705 patients with a history of RPL and re-examined after a 12-week interval in patients who tested positive. Persistent positive patients were administered low-dose aspirin during the subsequent pregnancy and clinical outcomes depending on the presence, type, and persistence of aPE were evaluated. Among the patients positive for aPE IgG and aPE IgM in the first examination (n = 117; 6.87%, and n = 235; 13.6%, respectively), 31.5% and 37.6% were negative upon re-examination, respectively. Moreover, among the cases with known pregnancy outcome, the miscarriage rate in the cumulative positive aPE group was 32.6% (29/89), which did not differ significantly from that of the aPE negative group (27.7%; 80/209; P = 0.178). Alternatively, the miscarriage rate in the persistently positive group was 40.7% (22/54), which was significantly higher than that in the transient positive group, 20.0% (7/35) (P = 0.041). Particularly, this difference become more significant when focusing on aPE IgM, 46.9% (15/32) in the persistent, compared with 16.7% (4/24) in the transient positive group (P = 0.024). aPE IgM is suggested to serve as a pathogenic aPL together with anti-cardiolipin antibodies and lupus anticoagulants, particularly if these factors persist over an extended period of time.

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  • Distribution of dendritic cells in the septate uterus: An immunological perspective. Reviewed International journal

    Yasuyuki Negishi, Masahiko Kato, Shuichi Ono, Yoshimitsu Kuwabara, Rimpei Morita, Hidemi Takahashi, Toshiyuki Takeshita

    American journal of reproductive immunology (New York, N.Y. : 1989)   83 ( 6 )   e13241   2020.3

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    PROBLEM: Septate uterus is associated with spontaneous abortion. Surgical intervention of the uterine septa (US) is frequently performed following spontaneous abortion; however, immunological mechanisms for spontaneous abortion in patients with septate uterus remain completely unknown. METHOD OF STUDY: A total of 12 women with septate uterus who underwent hysteroscopic metroplasty and 10 women with uterine leiomyoma who underwent total hysterectomy were enrolled as the experimental and control groups, respectively. Immune cells, dendritic cells (DCs), macrophages, T cells, natural killer cells, invariant natural killer cells, and chemokine receptors in US and uterine myometrium tissue (UMT) were analyzed using flow cytometry and immunohistochemical staining. Additionally, the chemokine production of macrophage inflammatory protein 1 alpha (MIP-1α), regulated upon activation normal T-cell express sequence (RANTES), and macrophage inflammatory protein 3 beta (MIP-3β) from the viable cells obtained from the US and UMT samples was evaluated in an ex vivo study. RESULTS: The percentage of CD141+ DCs in US was significantly lower than that in UMT. Both US and UMT showed CCR1 and CCR5 expression on CD141+ DCs; however, the production of chemokines, MIP-1α, RANTES, and MIP-3β was abundant in UMT-obtained viable cells. CONCLUSION: The accumulation of CD141+ DCs was lower in US than that in UMT. This phenomenon may be caused by low chemokine productions in US. Our findings support the benefit of surgical intervention for septate uterus-that is, the elimination of inappropriate implantation sites.

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  • Unique Clinical and Histological Features of Placental Mesenchymal Dysplasia Complicated by Severe Preeclampsia in the Midtrimester. Reviewed International journal

    Yoshimitsu Kuwabara, Mirei Yonezawa, Yumene Kubota, Tomoko Ichikawa, Ryuji Ohashi, Toshiyuki Takeshita

    AJP reports   10 ( 1 )   e113-e117   2020.1

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    Detailed clinical and pathological features of placental mesenchymal dysplasia (PMD) complicated by preeclampsia (PE) are unknown. A 39-year-old nulliparous woman was referred at 19 weeks gestation. Ultrasound examination identified a fetus with severe growth restriction (-2.8 SD) and a markedly thickened placenta with many cystic structures suggestive of PMD. At 21 weeks, the patient developed severe hypertension (180/95 mm Hg) with marked proteinuria and an elevated serum soluble fms-like tyrosine-kinase-1 (sFlt-1) level (47,000 pg/L). The pregnancy was terminated to protect maternal health. Placental weight was 450 g and no histopathological findings of either proliferation or dysplasia were observed in the trophoblast. Villous chromosome examination revealed a 46XX karyotype, consistent with the diagnosis of PMD. In addition to the pathological findings of vascular endothelial dysfunction characteristic of the placenta in PE cases, enhanced expression of sFlt-1 in the syncytiotrophoblast of the enlarged villi was confirmed by immunohistochemistry as a novel finding in this condition. Monitoring of the serum sFlt-1 value is suggested to be a useful predictor of the pathological change associated with extremely early severe PE in PMD cases.

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  • Assisted reproductive technology in Japan: A summary report for 2017 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology. Reviewed

    Osamu Ishihara, Seung Chik Jwa, Akira Kuwahara, Yukiko Katagiri, Yoshimitsu Kuwabara, Toshio Hamatani, Miyuki Harada, Tomohiko Ichikawa

    Reproductive medicine and biology   19 ( 1 )   3 - 12   2020.1

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    Purpose: The Japan Society of Obstetrics and Gynecology (JSOG) has collected cycle-based assisted reproductive technology (ART) data in an online registry since 2007. Herein, we present the characteristics and treatment outcomes of ART cycles registered during 2017. Methods: We collected cycle-specific information for all ART cycles implemented at participating facilities and performed descriptive analysis. Results: In total, 448,210 treatment cycles and 56,617 neonates (1 in 16.7 neonates born in Japan) were reported in 2017, increased from 2016; the number of initiated fresh cycles decreased for the first time ever. The mean patient age was 38.0 years (standard deviation 4.6). A total 110,641 of 245,205 egg retrieval cycles (45.1%) were freeze-all cycles; fresh embryo transfer (ET) was performed in 55,720 cycles. A total 194,415 frozen-thawed ET cycles were reported, resulting in 66,881 pregnancies and 47,807 neonates born. Single ET (SET) was performed in 81.8% of fresh transfers and 83.4% of frozen cycles, with singleton pregnancy/live birth rates of 97.5%/97.3% and 96.7%/96.6%, respectively. Conclusions: Total ART cycles and subsequent live births increased continuously in 2017, whereas the number of initiated fresh cycles decreased. SET was performed in over 80% of cases, and ET shifted from using fresh embryos to frozen ones.

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  • Is hysteroscopic metroplasty using the incision method for septate uterus a risk factor for adverse obstetric outcomes? Reviewed International journal

    Ono S, Kuwabara Y, Matsuda S, Yonezawa M, Watanabe K, Akira S, Takeshita T

    The journal of obstetrics and gynaecology research   45 ( 3 )   634 - 639   2019.3

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    AIM: This study aimed to assess whether hysteroscopic metroplasty using the incision method for septate uterus is a risk factor for adverse obstetric outcomes during pregnancy or delivery. METHODS: This retrospective, single-center cohort study of obstetric complications included 41 patients with recurrent pregnancy loss or unexplained infertility who underwent hysteroscopic metroplasty using the incision method for septate uterus. As controls, we recruited 1139 women who delivered at our hospital during the same period. The primary outcomes were mean weeks of delivery, mean birthweight, rate of cesarean section, rate of breech presentation, rate of post-partum hemorrhage, rate of preterm delivery, rate of placental abruption, rate of placenta previa, rate of placenta accreta and uterine rupture during pregnancy and delivery. RESULTS: The two groups did not differ in terms of age, mean weeks of delivery, mean birthweight, rate of post-partum hemorrhage, rate of preterm delivery, rate of placental abruption, rate of placenta previa or rate of placenta accreta. The rates of cesarean section and breech presentation were significantly higher in the study group than in the control group (56.1 vs 27.7%; P = 0.0002 and 19.5 vs 6.8%; P = 0.007, respectively). There were no cases of uterine rupture during pregnancy or delivery following hysteroscopic metroplasty. CONCLUSION: Hysteroscopic metroplasty using the incision method for septate uterus is not a risk factor for adverse obstetric outcomes. No severe complications, such as placenta abruption, placenta previa, placenta accreta, uterine rupture or heavy hemorrhage, were observed in the postoperative live birth group.

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  • Successful Management of Complicated Uterine DisplacementCaused by Unilateral Incarceration of the Bicornuate Uterus Reviewed International journal

    Ouchi N, Kuwabara Y, Yonezawa M, Kurashina R, Ichikawa T, Sawa Y, Toshiyuki Takeshita T

    Case Reports in Obstetrics and Gynecology   Article ID 320561   3205610 - 3205610   2019.3

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    Uterine incarceration is a serious complication of pregnancy, in which the gravid uterus becomes trapped in the posterior pelvis. When labor occurs, delivery does not progress, and the uterus may rupture. Therefore, preoperative diagnosis of uterine incarceration is important, and a caesarian section is indispensable except when the polarity of the uterus can be successfully restored. We report the case of a 35-year-old primipara with a complication of a bicornuate uterus who became pregnant after in vitro fertilization and embryo transfer. No abnormality was observed on regular checkups until the second trimester. At 28 weeks' gestation, the uterine cervix revealed marked dislocation, and, at 31 weeks, magnetic resonance imaging (MRI) revealed uterine cervix elongation and left horn incarceration. At 37 weeks' gestation, an elective cesarean section was performed. On laparotomy, the uterus was found to be markedly dislocated, and distended blood vessels were observed on the surface. Ultrasound examination was performed directly on the uterine wall to decide the incision site. After delivery of the baby, manual repositioning of the uterus revealed the unique concurrent clockwise rotation and retro-vertical deflection. Thus, we concluded that incarceration accompanied by a bicornuate uterus can cause complicated uterine displacement, and preoperative MRI and intraoperative ultrasound examination are useful for managing this condition.

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  • Innate immune cells in reproduction. Reviewed

    Negishi Y, Takahashi H, Kuwabara Y, Takeshita T

    The journal of obstetrics and gynaecology research   44 ( 11 )   2025 - 2036   2018.11

  • Efficacy of Dienogest in Thinning the Endometrium Before Hysteroscopic Metroplasty and Analysis of Postoperative Reproductive

    Shuichi Ono, Kenichiro Watanabe, Mirei Yonezawa, Tomoko Ichikawa, Yoshimitsu Kuwabara, Shigeo Akira, Toshiyuki Takeshita

    JOURNAL OF GYNECOLOGIC SURGERY   34 ( 5 )   234 - 238   2018.10

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    Objective: This study was conducted to evaluate the efficacy of preoperative dienogest for thinning the endometrium in patients undergoing hysteroscopic metroplasty for septate uteri and to analyze postoperative reproductive outcomes.Materials and Methods: This retrospective cohort study involved 51 patients, each with a history of at least two miscarriages, who underwent hysteroscopic metroplasty. Of the total patients, 16 were treated with 2mg/day of dienogest and 35 were not treated with dienogest. Primary outcome measures included: thickness of the endometrium on the day before surgery; operative time; hemoglobin and sodium levels on the day after hysteroscopic metroplasty; intraoperative amount of fluid infusion; and postoperative residual septum. Reproductive outcomes were analyzed by assessing pregnancy, miscarriage, and cumulative live birth rates. Dienogest, at 2mg/day, was orally administered as an extended regimen from cycle day 3 until the preoperative day.Results: There were significant differences in endometrium thickness on the day prior to surgery (dienogest group versus non-dienogest group: 6.62.0mm versus 10.0 +/- 2.3mm; p <= 0.0001), operative time (47.8 +/- 15.6 minutes versus 61.6 +/- 23.6 minutes; p=0.04), intraoperative amount of fluid infusion (2520.9 +/- 771.0mL versus 3254.1 +/- 1259.2mL; p=0.02). There were no significant differences in pregnancy, miscarriage, and cumulative live birth rates.Conclusions: This analysis suggests that dienogest is effective for thinning the endometrium before hysteroscopic metroplasty for septate uterus without lowering reproductive outcomes.

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  • Immunoproteomic identification of anti-C9 autoimmune antibody in patients with seronegative obstetric antiphospholipid syndrome Reviewed

    Yoshimitsu Kuwabara, Akira Katayama, Sachiko Kurihara, Hideo Orimo, Toshiyuki Takeshita

    PLoS ONE   13 ( 6 )   e0198472   2018.6

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    Immunoproteomic analysis was performed to identify unknown, pathology-related molecules in patients with seronegative (SN) obstetric antiphospholipid syndrome (APS) who clinically satisfied the diagnostic criteria for APS, but not the serological criteria. We collected peripheral blood from 13 SN-APS outpatients with known thrombotic predisposition, 13 with no known thrombotic predisposition, and four multiparous women with no history of miscarriage (control). Plasma proteins from volunteers were purified and used as plasma protein antigens. Two-dimensional immunoblotting was performed using pooled control or SN-APS serum samples as the primary antibodies. Mass spectrometry of reactive spots specific to SN-APS serum led to the identification of complement molecule C9. Western blotting using commercial purified alkylated C9 was performed to detect autoantibodies. Examination of individual patient serum identified reactivity in one patient with, and in two patients without known thrombotic predisposition. This study suggests that SN-APS pathologies were associated with autoantibodies that react to specific C9 epitopes.

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  • Retrospective cohort study of the risk factors for secondary infertility following hysteroscopic metroplasty of the uterine septum in women with recurrent pregnancy loss Reviewed

    Shuichi Ono, Mirei Yonezawa, Kenichiro Watanabe, Takashi Abe, Katsuya Mine, Yoshimitsu Kuwabara, Shigeo Akira, Toshiyuki Takeshita

    Reproductive Medicine and Biology   17 ( 1 )   77 - 81   2018.1

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    Purpose: A hysteroscopic metroplasty was performed for women with recurrent pregnancy loss owing to a uterine septum, following which some women became infertile. The aim of this study was to elucidate the risk factors of secondary infertility 1 year after hysteroscopic metroplasty for a uterine septum. Methods: A retrospective, single-center, cohort study included women with a history of at least two miscarriages that had been attributed to a uterine septum who underwent a hysteroscopic metroplasty. The patients’ background data were compared between the patients who conceived and those who remained infertile at 1 year postoperatively. The data were analyzed by using the Mann–Whitney U-test and multivariate analyses. Results: The postoperative live birth rate was 83.9% (n = 26), with persistent infertility in five women at 1 year. When comparing the pregnancy group with the infertile group, the women in the postoperative infertility group were significantly older than those in the postoperative pregnancy group. The multivariate analysis showed that age was an independent risk factor for persistent infertility. Conclusion: Age was identified as an independent risk factor for postoperative secondary infertility. Therefore, surgery as early as possible is recommended.

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  • Influence of perinatal low-dose acetylsalicylic acid therapy on fetal hemodynamics evaluated by determining the acceleration-time/ejection-time ratio in the ductus arteriosus Reviewed

    Miwa Miyazaki, Yoshimitsu Kuwabara, Toshiyuki Takeshita

    Journal of Obstetrics and Gynaecology Research   44 ( 1 )   87 - 92   2018.1

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    Aim: Acceleration-time/ejection-time ratio (At/Et ratio) of Doppler waveform is an established hemodynamic parameters that reflect proximal stenosis. Using this parameter, we evaluated whether perinatal low-dose acetylsalicylic acid (ASA) therapy could alter hemodynamics in the ductus arteriosus. Methods: Pulse Doppler measurements of the fetal ductus arteriosus were performed longitudinally from 20 to 37 gestational weeks in 106 healthy pregnant women (controls) and 65 pregnant women taking daily low-dose ASA (80 or 100 mg/day) because of a history of recurrent pregnancy loss. The At/Et ratio, pulsatility index (PI), and peak systolic velocity were evaluated and statistically analyzed. Results: The At/Et ratio significantly increased with gestational age in both the ASA group (r = 0.54) and the control group (r = 0.35), while the PI did not. Median peak systolic velocities also increased with gestational age in both the ASA group (r = 0.39) and the control group (r = 0.31). No significant differences in At/Et ratio, PI, or peak systolic velocity were observed between the ASA group and the control group. Conclusion: Administration of low-dose ASA during pregnancy did not appear to alter hemodynamics in the fetal ductus arteriosus.

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  • Diversity of progesterone action on lipopolysaccharide-induced expression changes in cultured human cervical fibroblasts according to inflammation and treatment timing Reviewed

    Yoshimitsu Kuwabara, Akira Katayama, Sachiko Kurihara, Marie Ito, Mirei Yonezawa, Nozomi Ouchi, Ryuhei Kurashina, Tomoko Ichikawa, Rintaro Sawa, Akihito Nakai, Hideo Orimo, Toshiyuki Takeshita

    AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY   78 ( 5 )   2017.11

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    ProblemThe effectiveness of progesterone (P4) treatment for preventing preterm births is unclear. Its effects on the uterine cervix were tested using cultured human uterine cervical fibroblasts (UCFs).
    Method of studyUCFs were incubated with lipopolysaccharide (LPS) in the presence or absence of P4 under various conditions. mRNA was subjected to PCR arrays and real-time RT-PCR to assess IL-6, IL-8, IL-1beta, PTGS2, MMP-1, and CXCL10 expression.
    ResultsWhen exposed to a high-LPS concentration (2.0g/mL), expression of these genes was not suppressed by simultaneous P4 (1.0mol/L) treatment, but it was significantly inhibited when P4 was administered 1hour prior to LPS, with the exception of the chemokines IL-8 and CXCL10. Expression of all genes was restricted by P4 under low-level LPS (0.2g/mL) stimulation, especially when administered prior to LPS treatment.
    ConclusionThese data suggest that early or prophylactic P4 administration is an effective and important measure for reducing preterm birth risk.

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  • Gonadotropin regulation and role of ovarian osteopontin in the periovulatory period Reviewed

    Yoshimitsu Kuwabara, Akira Katayama, Ryoko Tomiyama, Hu Piao, Sachiko Kurihara, Shuichi Ono, Katsuya Mine, Shigeo Akira, Hideo Orimo, Toshiyuki Takeshita

    JOURNAL OF ENDOCRINOLOGY   224 ( 1 )   49 - 59   2015.1

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    Osteopontin (OPN), a secreted glycoprotein, has multiple physiological functions. This study investigated the regulation and roles of OPN in the mouse ovary during the periovulatory stages. Immature female mice were treated with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) to simulate follicle maturation and ovulation. In situ hybridization and real-time RT-PCR were performed to assess expression of Opn in the periovulatory ovary. Granulosa cells (GCs) from PMSGprimed immature mice were cultured with or without hCG in the presence or absence of OPN, and effects on expression of Opn, progesterone synthesis, and vascular endothelial growth factor (VEGF) signaling were assessed by real-time RT-PCR, ELISA, and western blotting analysis. Opn transcripts were significantly upregulated 3 h after hCG treatment, followed by a peak at 16 h, and the transcripts localized to GCs. Incubation with hCG significantly increased quantities of Opn transcripts in GCs and OPN levels in the culture medium at 12 and 24 h. Furthermore, OPN treatment caused a significant increase in the levels of Star protein, P 450 cholesterol side-chain cleavage enzyme (p450scc), 3-betahydroxysteroid dehydrogenase (Hsd3b), and progesterone in the culture medium. OPN treatment promoted Vegf expression in GCs, which was significantly suppressed by a phosphoinositide 3-kinase (PI3K) inhibitor. In addition, OPN treatment stimulated phosphorylation of AKT, a downstream PI3K signaling molecule. In conclusion, expression of Opn was upregulated in mouse ovarian GCs in response to a gonadotropin surge through epidermal growth factor receptor signaling, which enhances progesterone synthesis and Vegf expression during the early-luteal phase.

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  • Rapid and Transient Upregulation of CCL11 (Eotaxin-1) in Mouse Ovary During Terminal Stages of Follicular Development Reviewed

    Yoshimitsu Kuwabara, Akira Katayama, Tsutomu Igarashi, Ryoko Tomiyama, Hua Piao, Reika Kaneko, Takashi Abe, Katsuya Mine, Shigeo Akira, Hideo Orimo, Toshiyuki Takeshita

    AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY   67 ( 5 )   358 - 368   2012.5

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    Problem This study aimed to investigate the regulation of expression, localization and physiological role of the CCL11/ CCR3 axis in mouse ovary during the periovulatory period. Method of study CCL11/ CCR3 expression in the mouse ovary after treatment with pregnant mare serum gonadotropin (PMSG) followed by human chorionic gonadotropin (hCG) 48 hr later was assessed in vivo and in 3-dimensional cultures in vitro. Results Real-time RT-PCR analyses revealed transient CCL11 mRNA upregulation 6 hr after hCG treatment. Immunohistochemical staining of serial ovarian sections demonstrated overlapping expression of CCL11, CCR3 and CD31 endothelial cell marker in the theca-interstitial layer at 10 hr after hCG treatment. In vitro 3-dimensional cultures of periovulatory ovarian tissues demonstrated that treatment with anti-CCL11 neutralizing antibody significantly decreased CD31 transcript. Conclusions Gonadotropin surge leads to transient CCL11/ CCR3 axis upregulation in the ovarian theca-interstitial layer, suggesting that it is involved in periovulatory physiological processes by affecting follicular vessels.

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  • Ritodrine-induced Pustular Eruptions Distinctly Resembling Impetigo Herpetiformis Reviewed

    Yoshimitsu Kuwabara, Atsuki Sato, Hiroko Abe, Sumino Abe, Naoki Kawai, Toshiyuki Takeshita

    JOURNAL OF NIPPON MEDICAL SCHOOL   78 ( 5 )   329 - 333   2011.10

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    A 27-year-old nulligravida woman without a history of dermatosis was hospitalized for threatened preterm labor at 29 weeks' gestation; therefore, continuous infusion of ritodrine hydrochloride was started. At 31 weeks' gestation, erythematous plaques appeared and spread over the body surface; therefore, a topical steroid preparation was applied. At 32 weeks' gestation, the eruptions developed into irregular annular areas of erythema with multiple pustules accompanied by severe itching, and oral prednisolone treatment was started. Bacterial cultures of the pustules were negative, and a crural cutaneous biopsy revealed Kogoj's spongiform pustules. Based on the clinicopathological findings, the most likely diagnosis was impetigo herpetiformis, which causes cutaneous symptoms closely resembling pustular psoriasis in pregnant females without a history of psoriasis. To rule out ritodrine-induced pustular eruptions, the ritodrine infusion was stopped and treatment with an MgSO4 preparation was started at 33 weeks' 3 days' gestation; however, the uterine contractions could not be suppressed. Because of the patient's highly edematous, severely painful feet, a cesarean section was performed the same day. Within several days of delivery, the eruptions began to resolve, and no recurrence was observed after treatment with oral prednisolone was stopped 31 days after delivery. On the basis of a positive patch test for ritodrine. we diagnosed pustular drug eruptions caused by ritodrine hydrochloride. Although ritodrine-induced pathognomonic cutaneous eruptions are rare, we would like to emphasize that ritodrine can cause drug-induced pustular eruptions distinctly resembling life-threatening impetigo herpetiformis. (J Nippon Med Sch 2011; 78: 329-333)

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  • Proteomic approach to identify-specific molecules related to ovarian steroid hormone-dependent diseases. Reviewed

    Kuwabara, Y, Takeshita T

    J Nippon Med Sch   78 ( 1 )   57 - 59   2011

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  • Proteomic Analyses of Recombinant Human Follicle-Stimulating Hormone and Urinary-Derived Gonadotropin Preparations Reviewed

    Yoshimitsu Kuwabara, Katsuya Mine, Akira Katayama, Tomoko Inagawa, Shigeo Akira, Toshiyuki Takeshita

    JOURNAL OF REPRODUCTIVE MEDICINE   54 ( 8 )   459 - 466   2009.8

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    OBJECTIVE: To understand the properties of each available gonadotropin preparation, especially in terms of the differences between urinary-derived and recombinant preparations.
    STUDY DESIGN: Human menopausal gonadotropin (hMG), highly purified urinary-derived follicle-stimulating hormone (uFSH-HP) and recombinant FSH (rFSH) were subjected to 2-dimensional gel electrophoresis (2-DE), and protein spots were visualized by silver-staining procedures. Major spots were analyzed by mass spectrometry. Fluorescent-labeled preparations were also subjected to 2-DE to evaluate the quantities of FSH isohormones contained in each preparation.
    RESULTS: 2-DE and mass spectrometry analyses of hMG identified many extracellular proteins as major impurities and several plasma membrane proteins including prion proteins. Both uFSH-HP and rFSH demonstrated slight impurities and showed several alpha and beta subunit isohormones. rFSH contained higher amounts of the basic isohormones of the alpha subunit than uFSH-HP, whereas the predominance of the basic isohormones was less significant in the 0 subunit.
    CONCLUSION: Proteomic analyses demonstrated the detailed protein profiles of each preparation. Differences in the quantities of a subunit isohormones may contribute to the variations in FSH activity observed between recombinant and urinary-derived FSH preparations. (J Reprod Med 2009;54: 459-466)

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  • Efficacy of long-term, low-dose gonadotropin-releasing hormone agonist therapy (draw-back therapy) for adenomyosis Reviewed

    Shigeo Akira, Katsuya Mine, Yoshirnitsu Kuwabara, Toshiyuki Takeshita

    MEDICAL SCIENCE MONITOR   15 ( 1 )   CR1 - CR4   2009.1

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    Background: The usefulness of long-term, low-dose gonadotropin-releasing hormone agonist (GnPHa; buserelin acetate) therapy, so-called draw-back therapy, for the treatment of adenomyosis was investigated.
    Material/Methods: A retrospective observational study was conducted covering the period between January 2003 and March 2008. The subjects consisted of 12 patients with adenomyosis Who Underwent draw-back therapy for 2 years and had previously received GnRHa. GnRHa was initiated at 900 mu g/day (6 nasal sprays/day). When the CA-125 level normalized, the GnRHa dosage was adjusted to 150-750 mu g/day to achieve a plasma estradiol (E 2) concentration of 20-50 pg/ml (i.e., the therapeutic window). Pain during withdrawal bleeding and chronic pelvic pain were assessed using a Visual analogue scale. In addition, bone mineral density (BMD) of the lumbar vertebrae was measured using dual-energy X-ray absorptiometry.
    Results: The mean GnRHa dose during draw-back therapy was 435 mu g/day (2.9 nasal sprays/day). The mean E 2 level during draw-back therapy was 36.3 +/- 14.3 mu g/ml. The intensity of chronic pelvic pain was significantly lower during draw-back therapy than before draw-back therapy, and was nearly eliminated in many patients (4.8 +/- 1.2 vs. 0.6 +/- 0.7, respectively [p=0.000]). Compared to the severity of vasomotor symptoms during previous regular GnRHa therapy, the severity of vasomotor symptoms during draw-back therapy was significantly lower (3.8 +/- 0.7 vs 1.1 +/- 0.7, respectively [p=0.000]). The decrease in BMD during a 6-month course of treatment was 0.96 +/- 0.9%.
    Conclusions: GnRHa draw-back therapy allowed maintenance of plasma E, levels within the therapeutic Window. GnRHa call thus be administered for long periods of time while maintaining therapeutic effects oil adenomyosis and suppressing adverse events.

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  • Successful long-term management of adenomyosis associated with deep thrombosis by low-dose gonadotropin-releasing hormone agonist therapy Reviewed

    S. Akira, N. Iwasaki, M. Ichikawa, K. Mine, Y. Kuwabara, T. Takeshita, H. Tajima

    CLINICAL AND EXPERIMENTAL OBSTETRICS & GYNECOLOGY   36 ( 2 )   123 - 125   2009

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    We report the case of a patient with adenomyosis complicated by deep vein thrombosis in whom low-dose gonadotropin-releasing hormone agonist (GnRHa) therapy was useful as a uterus-conserving therapeutic option. The patient was a 34-year-old nulliparous woman who presented with edema and pain in the left lower leg. The patient had been treated with four cycles of GnRHa therapy for adenomyosis and repeatedly experienced chronic pelvic pain, dysmenorrhea and anemia due to hypermenorrhea. Leg venography confirmed deep vein thrombosis, and thrombolytic therapy was performed to eliminate symptoms. Because the patient strongly wanted to conserve the uterus, low-dose GnRHa therapy was initiated. The patient is Currently taking 450 mu g/clay buserelin acetate nasally (regular close: 900 mu g/day), and estradiol levels have been maintained at 24-50 pg/ml. Anemia, leg numbness and chronic pelvic pain have dissipated, and the patient has not experienced estrogen deficiency symptoms for more than two years.

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  • Proteome analysis of human placentae: Pre-eclampsia versus normal pregnancy Reviewed

    K. Mine, A. Katayama, T. Matsumura, T. Nishino, Y. Kuwabara, G. Ishikawa, T. Murata, R. Sawa, Y. Otsubo, S. Shin, T. Takeshita

    PLACENTA   28 ( 7 )   676 - 687   2007.7

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    Although placental proteins play multiple roles in fetal and placental development and in the maintenance of pregnancy, many remain inadequately characterized. In the present study, we comprehensively analyzed these proteins by using a proteomic approach. Samples were denatured with guanidine hydrochloride, which was found to be superior to the commonly used urea for the present purpose, and subjected to 2-dimensional (2D) electrophoresis (2-DE) to obtain placental proteome maps. The identified protein spots (ca. 60% of the total) on the proteome maps included several pregnancy-related proteins (PRPs). Furthermore, a novel 2D immunoblotting (2-DI) analysis of molecules related to pre-eclampsia revealed three immunopositive spots that appeared to correspond to dynactin p-50, a protein related to cell tum-over. The rate of positivity for dynactin p-50-reactive antibodies was significantly (P = 0.0024) higher in 26 pre-eclamptic women than in 58 normally pregnant women. These results indicate that dynactin p-50 may be involved in the pathophysiology of pre-eclampsia. (C) 2006 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.placenta.2006.10.005

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  • Heterodimeric fly glycoprotein hormone-alpha 2 (GPA2) and glycoprotein hormone-beta 5 (GPB5) activate fly leucine-rich repeat-containing G protein-coupled receptor-1 (DLGR1) and stimulation of human thyrotropin receptors by chimeric fly GPA2 and human GPB5 Reviewed

    S Sudo, Y Kuwabara, JI Park, SY Hsu, AJW Hsueh

    ENDOCRINOLOGY   146 ( 8 )   3596 - 3604   2005.8

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    Glycoprotein hormones play important roles in thyroid and gonadal function in vertebrates. The glycoprotein hormone alpha-subunit forms heterodimers with different beta-subunits to activate TSH or gonadotropin (LH and FSH) receptors. Recent genomic analyses allowed the identification of another alpha-subunit, GPA2, and another beta-subunit, GPB5, in human, capable of forming heterodimers to activate TSH receptors. Based on comparative genomic searches, we isolated the fly orthologs for human GPA2 and GPB5, each consisting of 10 cysteine residues likely involved in cystine-knot formation. RT-PCR analyses in Drosophila melanogaster demonstrated the expression of GPA2 and GPB5 at different developmental stages. Immunoblot analyses further showed that fly GPA2 and GPB5 subunit proteins are of approximately 16 kDa, and coexpression of these subunits yielded heterodimers. Purified recombinant fly GPA2/GPB5 heterodimers were found to be glycoproteins with N-linked glycosylated alpha-subunits and nonglycosylated alpha-subunits, capable of stimulating cAMP production mediated by fly orphan receptor DLGR1 but not DLGR2. Although the fly GPA2/GPB5 heterodimers did not activate human TSH or gonadotropin receptors, chimeric fly GPA2/human GPB5 heterodimers stimulated human TSH receptors. These findings indicated that fly GPA2/GPB5 is a ligand for DLGR1, thus showing the ancient origin of this glycoprotein hormone-seven transmembrane receptor-G protein signaling system. The fly GPA2 also could form heterodimers with human GPB5 to activate human TSH receptors, indicating the evolutionary conservation of these genes and suggesting that the GPA2 subunit may serve as a scaffold for the beta-subunit to activate downstream G protein-mediated signaling.

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  • Neonatal lethality of LGR5 null mice is associated with ankyloglossia and gastrointestinal distension Reviewed

    H Morita, S Mazerbourg, DM Bouley, CW Luo, K Kawamura, Y Kuwabara, H Baribault, H Tian, AJW Hsueh

    MOLECULAR AND CELLULAR BIOLOGY   24 ( 22 )   9736 - 9743   2004.11

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    The physiological role of an orphan G protein-coupled receptor, LGR5, was investigated by targeted deletion of this seven-transmembrane protein containing a large N-terminal extracellular domain with leucine-rich repeats. LGR5 null mice exhibited 100% neonatal lethality characterized by gastrointestinal tract dilation with air and an absence of milk in the stomach. Gross and histological examination revealed fusion of the tongue to the floor of oral cavity in the mutant newborns and immunostaining of LGR5 expression in the epithelium of the tongue and in the mandible of the wild-type embryos. The observed ankyloglossia phenotype provides a model for understanding the genetic basis of this craniofacial defect in humans and an opportunity to elucidate the physiological role of the LGR5 signaling system during embryonic development.

    DOI: 10.1128/MCB.24.22.9736-9743.2004

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  • Intrauterine therapy for the acutely enlarging fetal cystic hygroma Reviewed

    Y Kuwabara, R Sawa, Y Otsubo, Y Yoneyama, H Asakura, T Araki, T Takeshita

    FETAL DIAGNOSIS AND THERAPY   19 ( 2 )   191 - 194   2004

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    Enlarged fetal cystic hygroma is known to cause life-threatening complications such as fetal hydrops and neonatal respiratory difficulty. A 28-year-old Japanese woman, gravida 0, presented with fetal cystic hygroma at 23 weeks of gestation. There were no other structural malformations or hydrops detected by ultrasonographic examination. In addition, the karyotype was diagnosed as normal through amniotic fluid analysis. The cystic lesion showed acute enlargement and intrauterine sclerotherapy using OK-432 was performed at 26 weeks. The size of the cyst initially decreased, which was followed by a gradual increase. A viable 3,098 g male infant was delivered by cesarean section at 37 weeks without any other complications. The infant had no clinical difficulty during the neonatal period and later underwent a surgical removal of the remaining cystic lesion. Cases of fetal cystic hygroma showing acute enlargement without other complications are considered good candidates for intrauterine therapy to prevent subsequent complications. Copyright (C) 2004 S. Karger AG, Basel.

    DOI: 10.1159/000075149

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  • Unique amino acids cluster for switching from the dehydrogenase to oxidase form of xanthine oxidoreductase Reviewed

    Y Kuwabara, T Nishino, K Okamoto, T Matsumura, BT Eger, EF Pai, T Nishino

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   100 ( 14 )   8170 - 8175   2003.7

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    In mammals, xanthine oxidoreductase is synthesized as a dehydrogenase (XDH) but can be readily converted to its oxidase form (XO) either by proteolysis or modification of cysteine residues. The crystal structures of bovine milk XDH and XO demonstrated that atoms in the highly charged active-site loop (Gln-423-Lys-433) around the FAD cofactor underwent large dislocations during the conversion, blocking the approach of the NAD+ substrate to FAD in the XO form as well as changing the electrostatic environment around FAD. Here we identify a unique cluster of amino acids that plays a dual role by forming the core of a relay system for the XDH/XO transition and by gating a solvent channel leading toward the FAD ring. A more detailed structural comparison and site-directed mutagenesis analysis experiments showed that Phe-549, Arg-335, Trp-336, and Arg-427 sit at the center of a relay system that transmits modifications of the linker peptide by cysteine oxidation or proteolytic cleavage to the active-site loop (Gln-423-Lys-433). The tight interactions of these residues are crucial in the stabilization of the XDH conformation and for keeping the solvent channel closed. Both oxidative and proteolytic generation of XO effectively leads to the removal of Phe-549 from the cluster causing a reorientation of the bulky side chain of Trp-336, which then in turn forces a dislocation of Arg-427, an amino acid located in the active-site loop. The conformational change also opens the gate for the solvent channel, making it easier for oxygen to reach the reduced FAD in XO.

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  • Changes in the proportion of T helper 1 and T helper 2 cells in cord blood after premature rupture of membranes Reviewed

    Y. Yoneyama, S. Suzuki, R. Sawa, Y. Otsubo, A. Miura, Y. Kuwabara, H. Ishino, Y. Kiyokawa, D. Doi, K. Yoneyama, T. Araki

    Archives of Gynecology and Obstetrics   267 ( 4 )   217 - 220   2003.2

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    This study investigated changes in the proportion of T helper (Th)1 and Th2 cells in cord blood after premature rupture of membranes (PROM), and evaluate the effects of PROM on the intrauterine fetal immune status. The proportion of CD3-positive T cells secreting interferon (IFN)-γ as an index of Th1 cells, and interleukin (IL)-4 as an index of Th2 cells in cord blood of 12 newborns with and without PROM, were analyzed by flow cytometry. In cord blood of newborns with PROM, the proportion of IFN-γ secreting cells significantly increased, and the proportion of IL-4 secreting cells was rather high but not significantly higher than that of newborns without PROM. These changes eventually caused a shift in the Th1/Th2 ratio to Th1 dominance in PROM. There was no significant correlation between the proportion of IFN-γ secreting cells and the duration of PROM before the onset of labor. These results suggest that the increase in the proportion of IFN-γ secreting cells after PROM, which eventually cause the Th1/Th2 ratios to show the Th1 predominance, may reflect in part intrauterine fetal immune responses to PROM.

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  • Critical pulmonary stenosis with intact ventricular septum and fetal arrhythmias Reviewed

    Yoshimitsu Kuwabara, Yoshio Shima, Masato Takeuchi, Tsuguo Shinohara, Kouichi Awataguchi, Tsutomu Araki, Sumio Shin

    Archives of Gynecology and Obstetrics   267 ( 4 )   236 - 238   2003.2

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    A 23-year-old woman, gravida 1, was referred to our hospital for possible fetal distress at 32 weeks of pregnancy, A fetal cardiotochogram showed a reactive pattern, but mild continuous bradycardia and an intermittent pulse were observed, regarded as a sinus type and a type of A-V block, respectively. The continuous deceleration of the heart rate to 95 bpm was observed frequently at 35 weeks, 3 days of gestation. Thus, an emergent cesarean section was performed and a viable 2,082 g female infant was delivered. The neonate gradually became cyanotic, and an echocardiogram was performed. The neonate was regarded as a right ventricular outflow obstruction with intact ventricular septum. Unlike other cases, the infant revealed a moderately developed right ventricle despite a severely stenotic tricuspid valve. The infant died 27 days after birth and an autopsy established the diagnosis of critical pulmonary stenosis with intact ventricular septum. Right ventricular myocardial sinusoidal-coronary artery connections, one of the major features of this type of heart anomaly, was speculated to be involved in the cause of fetal bradyarrhythmias.

    DOI: 10.1007/s00404-002-0307-6

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  • Serum adenosine deaminase activity and its isoenzyme pattern in women with normal pregnancies Reviewed

    Y. Yoneyama, S. Suzuki, R. Sawa, Y. Otsubo, A. Miura, Y. Kuwabara, H. Ishino, Y. Kiyokawa, D. Doi, K. Yoneyama, T. Araki

    Archives of Gynecology and Obstetrics   267 ( 4 )   205 - 207   2003.2

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    Adenosine deaminase (ADA) is a purine enzyme which is essential for the proliferation, maturation and function of lymphoid cells, and congenital deficiency of this enzyme is associated with severe combined immunodeficiency disease. The activity of ADA has changed in diseases characterized by the alteration of cell-mediated immunity such as rheumatoid arthritis, systemic lupus erythematosus and tuberculosis, so ADA has been considered as a nonspecific marker of cellmediated immunity. In this study we examined changes in serum total ADA activity and the patterns of two ADA isoenzymes, ADA1 and ADA2 in normal pregnant women, and evaluated the possible role of the alteration of cell-mediated immunity during normal pregnancy as causes of changes in ADA activity. We measured serum activities of total ADA, ADA1 and ADA2 in normal pregnant women in the third trimester (n=24) and age-matched healthy nonpregnant women (n=24). Peripheral blood lymphocytes and monocytes were also measured. In normal pregnant women, serum total ADA activity averaged 10.5 ± 0.5 U/L, which was significantly lower than in nonpregnant women (14.0 ± 0.5 U/L) (p&lt
    0.05), and mean serum ADA2 activity also significantly reduced that of nonpregnant women (p&lt
    0.05). There was no significant difference in ADA1 activity in normal pregnant and nonpregnant women. The decrease in total ADA activity was accompanied by the decrease in lymphocyte count. These results suggest that reduced serum total ADA activity reflects decrease in ADA2 activity, and which may be in part associated with depressed cellmediated immunity during normal pregnancy.

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  • Characteristic prenatal ultrasonographic findings of patent urachus: A case report Reviewed

    Yoshio Shima, Mari Hayashida, Takashi Hayashi, Yoshimitsu Kuwabara, Tsutomu Araki

    Journal of Nippon Medical School   70 ( 2 )   172 - 174   2003

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    A characteristic prenatal ultrasonographic finding of patent urachus is described. Routine obstetrical ultrasonography first revealed a cystic mass in the umbilical cord at 16 weeks of gestation. The mass spontaneously decreased in size and was undetectable at full term on serial ultrasound examination. The male newborn infant was delivered uneventfully at 38 weeks of gestation, weighing 2,774 g. He was noted to void urine from the umbilicus soon after birth, and, the diagnosis of patent urachus was confirmed. On the 8 th day of life, complete surgical removal of the urachus was performed, and the postoperative course was uneventful. An umbilical cystic mass which diminishes in size over the course of pregnancy is a sugesstive prenatal sonographic finding for urachal anomalies.

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  • Plasma 5 '-nucleotidase activities and uric acid levels in women with pre-eclampsia Reviewed

    Y Yoneyama, S Suzuki, R Sawa, Y Otsubo, A Miura, Y Kuwabara, H Ishino, Y Kiyokawa, D Doi, H Kobayashi, T Araki

    GYNECOLOGIC AND OBSTETRIC INVESTIGATION   54 ( 3 )   168 - 171   2002

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    The present study investigated plasma activity of 5'-nucleotidase, a key enzyme in the production of adenosine, in pre-eclampsia, and evaluated the relationship between changes in 5'-nucleotidase activity, and levels of uric acid, endproduct of the purine metabolism, and the severity of pre-eclampsia. We measured plasma 5'-nucleotidase activities and uric acid levels in women with 18 normal pregnancies, mild and severe preeclampsia. In mild and severe pre-eclampsia, plasma 5'-nucleotidase activities and uric acid levels were significantly increased compared with those in normal pregnancy (p &lt; 0.05). Plasma 5'-nucleotidase activity increased according to increases in uric acid levels and the severity of pre-eclampsia. These results suggest that increased plasma 5'-nucleotidase activity may, at least in part, be related to changes in purine metabolism in pre-eclampsia. Copyright (C) 2002 S. Karger AG, Basel.

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  • Newborn with transverse facial cleft associated with polyhydramnios Reviewed

    Yoshio Shima, Koichi Ogawa, Yoshimitsu Kuwabara, Nobuyuki Takechi, Sumio Shin

    Journal of Perinatology   22 ( 1 )   91 - 92   2002

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    We describe here the case of a female newborn baby with a bilateral complete transverse facial cleft. Obstetrical ultrasound had revealed an increased amount of amniotic fluid from 28 weeks' gestation without fetal hydrops or congenital anomalies. A 1900-g baby girl born at 36 weeks' gestation presented with bilateral wide facial clefts with macrostomia, microphthalmia, nose, and auricular deformities. Her breathing was dependent on life support, which was discontinued 2 hours after birth. An autopsy revealed no congenital malformations in vital organs but the absence of the olfactory nerves. Polyhydramnios and respiratory arrest after birth were presumed to be due to central disintegration of swallowing and breathing, in this case with brain anomaly.

    DOI: 10.1038/sj/jp/7210595

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  • Regulation of plasma adenosine levels in normal pregnancy Reviewed

    Y Yoneyama, R Sawa, S Suzuki, H Ishino, A Miura, Y Kuwabara, T Kuwajima, N Ito, Y Kiyokawa, Y Otsubo, T Araki

    GYNECOLOGIC AND OBSTETRIC INVESTIGATION   53 ( 2 )   71 - 74   2002

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    The aim of this study was to investigate the possible mechanism of the regulation of plasma adenosine concentration [ADO] in normal pregnancy. We measured the activities of circulating enzymes that are involved in the production and metabolism of adenosine, and plasma [ADO] in nonpregnant (n = 14) and normal pregnant women (n = 14) in the third trimester. In pregnant women, the activity of plasma 5'-nucleotidase and plasma [ADO] were significantly elevated and plasma adenosine deaminase activity was significantly reduced. Enzymatic activities of both plasma enzymes appear to be changed in a way that would favor increased adenosine concentrations. Copyright (C) 2002 S. Karger AG, Basel.

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  • Serum adenosine deaminase activity in women with pre-eciampsia Reviewed

    Y Yoneyama, R Sawa, S Suzuki, Y Otsubo, A Miura, Y Kuwabara, H Ishino, Y Kiyokawa, D Doi, K Yoneyama, H Kobayashi, T Araki

    GYNECOLOGIC AND OBSTETRIC INVESTIGATION   54 ( 3 )   164 - 167   2002

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    The present study investigated serum adenosine deaminase (ADA) activity and the patterns of two ADA isoenzymes, ADA1 and ADA2, and to evaluate the possible role of cell-mediated immunity as causes of the changes in ADA activity in pre-eclampsia. We measured serum activities of total ADA, ADA1 and ADA2 in pre-eclampsia (n = 22) and normal pregnancy (n = 22). Peripheral blood monocyte counts and neopterin levels, reflecting the activation of the monocyte-macrophage cell system, were also measured. In pre-eclampsia, serum total ADA and ADA2 activities were significantly increased compared with normal pregnancy (p &lt; 0.05), which were accompanied by increases in serum neopterin levels. These results suggest that increased total ADA activity reflects increases in ADA2 activity, which may be in part related to enhanced cell-mediated immunity during preeclampsia. Copyright (C) 2002 S. Karger AG, Basel.

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  • Mesenchymal stem villous hyperplasia of the placenta and fetal growth restriction Reviewed

    Y Kuwabara, Y Shima, T Araki, S Shin

    OBSTETRICS AND GYNECOLOGY   98 ( 5 )   940 - 943   2001.11

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    BACKGROUND: Mesenchymal stem villous hyperplasia of the placenta is a rare placental anomaly characterized by placental vascular malformation and the appearance of a partial mole.
    CASE: A multiparous woman presented with fetal growth restriction (FGR) at 35 weeks' gestation. Ultrasonographic examination showed multiple anechoic lesions on the placental surface. Cesarean delivery was performed at 37 weeks' gestation, and a healthy 1536-g female was delivered. The placenta had aneurysmal dilatations of the chorionic vessels. Unlike other cases, it also showed subamniotic hemorrhage and had no features of a partial mole. Histologic examination established the diagnosis of mesenchymal stem villous hyperplasia of the placenta with severe thrombosis.
    CONCLUSION: Fetal growth restriction can be caused by severe thrombosis in this placental anomaly. (Obstet Gynecol 2001;98:940-3. (C) 2001 by the American College of Obstetricians and Gynecologists.).

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Research Projects

  • 慢性子宮内膜炎におけるエピジェネティック変容とプロゲステロン不応機序の解明

    Grant number:22K09559  2022.4 - 2026.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    桑原 慶充

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    Grant amount:\4030000 ( Direct Cost: \3100000 、 Indirect Cost:\930000 )

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  • 新たな視点から調節卵巣刺激への反応性を予測する血中オステオポンチンの測定意義

    Grant number:22K09584  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    中尾 仁彦

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

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  • 原因不明不育症おける“ネオセルフ”抗体産生機構による病原性自己抗体-抗原の探索

    Grant number:21K09478  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    片山 映, 桑原 慶充, 杉田 洋佑

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    原因不明の不育症患者の内、自己免疫疾患の臨床所見を示すが、病態と関連する既知の自己抗体が検出されない血清学的陰性リン脂質抗体症候群(SN-APS)が一定数含まれる。自己免疫疾患である抗リン脂質抗体症候群は、不育症におけるリスク因子であり、SN-APSにおいても未知の自己抗体が病因として強く関与していることが示唆されている。本研究は、自己免疫疾患の関与が示唆される、SN-APS患者において、ネオ・セルフ抗体産生機構に基づいた、病因となる未知の自己抗原の探索と、その検出法の確立を進めている。
    ネオ・セルフ抗体の産生は、炎症刺激等により、自己のミスフォールドタンパク質が、非免疫細胞である血管内皮細胞等で抗原提示されることに起因している。そこで、SN-APS患者由来のiPS細胞を、血管内皮細胞へ分化誘導した後、炎症刺激によって提示されるタンパク質の検出法の確立を目的として、まずiPS化済みの細胞を用いた検討を行った。分化誘導した血管内皮細胞で、炎症刺激(INFγ)により抗原提示を行う主要組織適合遺伝子複合体(MHC)クラスII分子の検出が確認された。さらに、MHCクラスII抗体を用いた免疫沈降と質量分析により、炎症刺激時に特異的にMHCクラスIIと複合体を形成するタンパク質の発現を確認した。

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  • New therapeutic strategies for miscarriage and preterm birth by regulation of innate immunity

    Grant number:20K09679  2020.4 - 2023.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

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    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

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  • Novel mechanism of endometrial ovarian cyst related to sterile inflammation

    Grant number:19K09813  2019.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Ikeda Mariko

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    This study aimed to investigate the involvement of high-mobility group box-1 (HMGB1) in an inflammatory milieu and the characteristics of immune cells in endometrial ovarian cyst (EOC). The cytoplasmic HMGB1 levels in dendritic cells (DCs), macrophages, and non-immune cells were analyzed by flow cytometry. We also evaluated the proportions of immune, T, NK, iNKT, NK, and regulatory T (Treg) cells. Results showed that the DCs, macrophages, and non-immune cells of EOC had significantly higher cytoplasmic HMGB1 levels than those of non-EOC (nEOC). The expression of CD69 and CD107a on CD8+ T and CD4+ T cells of EOC was also more enhanced than that of nEOC. Furthermore, the M2 macrophages and Tregs highly accumulated in EOC. These results indicate that HMGB1 may aggravate chronic inflammation related to T-cell activation and simultaneously facilitate development of the immunosuppressive milieu in EOCs.

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  • Sterile Inflammation - A novel approach to preterm birth -

    Grant number:19K08331  2019.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    SHIMA YOSHIO

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    Grant amount:\3900000 ( Direct Cost: \3000000 、 Indirect Cost:\900000 )

    Preterm birth remains a major health issue in Japan, despite its high levels of standard care. Infection has been considered as a central role in preterm births and their consequence, however, it is not proven in many cases in practice. The research focused on inflammation evoked by self-component around the perinatal period, with the results that endogenous molecular patterns in placental tissue or clinical specimens from preterm infants activated innate immune system and contributed to pathophysiology.

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  • 新たな早産予防戦略を指向した、子宮頸管における無菌性炎症とその制御機構の解明

    Grant number:18K09239  2018.4 - 2022.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    桑原 慶充, 片山 映, 竹下 俊行

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    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    子宮頸管における無菌性炎症応答とプロゲステロンによる制御系の破綻により誘導される早産病態メカニズムの検証を目指して以下の検討を行った。
    ①無菌性炎症応答に関与する内因性リガンドの探索:頸管組織にも存在する代表的なAlarminであるHMGB1を各種濃度で子宮頸部線維芽細胞(UCFs)培養系に添加したところ、推定される生理的濃度では炎症応答は惹起されず、他の内因性リガンドの探索が必要と考えられた。Alarminの細胞外放出は、組織損傷などによる受動的な漏出以外に、炎症刺激による能動的な産生が報告されている。UCFs培養におけるLPS誘導性の炎症誘導性分子のうち、プロゲステロンによって発現が抑制されるリガンドをRNA シークエンス法を用いてグローバルに解析すると、先行研究で報告した分子群(IL-6, IL-8, PTGS2, CXCL11等)に加え、Alarminとして報告されている炎症メディエーターが新規に同定された。この分子の発現は頸管組織においてプロゲステロン作用で制御されている可能性が示唆され、無菌性炎症応答に関与する内因性リガンド候補と位置付けた。
    ②無菌性炎症と拮抗するプロゲステロン標的分子の探索:頸管熟化機構において、炎症応答と呼応したプロゲステロン作用の減弱が推定される。そこで、RNAシークエンス法のデータより、プロゲステロン単独投与で著明に発現誘導され、LPS添加によって抑制される分子群を抽出した。さらにハンドサーチにより、炎症応答カスケードに抑制的に作用するシグナル分子を同定した。この分子はプロゲステロンシグナルの標的として頸管組織における潜在性無菌性炎症と拮抗している可能性が示唆される。

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  • Analysis of possible mechanism of miscarriage in women with septate uterus

    Grant number:18K09304  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Takeshita Toshiyuki

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    Grant amount:\3250000 ( Direct Cost: \2500000 、 Indirect Cost:\750000 )

    Septate uterus is associated with spontaneous abortion. However, immunological mechanisms for miscarriage in patients with septate uterus remain completely unknown. Immune cells, dendritic cells (DCs), macrophages, T cells, natural killer cells, invariant natural killer cells, and chemokine receptors in US and uterine myometrium tissue (UMT) were analyzed using flow cytometry and immunohistochemical staining. The percentage of CD141+ DCs in US was significantly lower than that in UMT. Both US and UMT showed CCR1 and CCR5 expression on CD141+ DCs; however, the production of chemokines, MIP-1α, RANTES, and MIP-3β was abundant in UMT-obtained viable cells. The accumulation of CD141+ DCs was lower in US than that in UMT. This phenomenon may be caused by low chemokine productions in US. Our findings support the benefit of surgical intervention for septate uterus-that is, the elimination of inappropriate implantation sites.

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  • A basic and clinical approach to risk factors of recurrent pregnancy loss &#8211; Identification of a novel antibody associated with seronegative obstetric antiphospholipid syndrome (SN-APS)

    Grant number:25462578  2013.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Takesshita Toshiyuki

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    Grant amount:\4940000 ( Direct Cost: \3800000 、 Indirect Cost:\1140000 )

    There is a subpopulation of patients with clinical symptoms of APS, but the lack of serological markers (seronegative APS). We collected peripheral blood from SN-APS outpatients with known thrombotic predisposition (protein S deficiency, protein C deficiency, factor XII deficiency, or presence of anti-phosphatidylethanolamine antibodies). Two-dimensional immunoblotting was performed with pooled control and SN-APS sera as the primary antibody, and complement molecule C9 were identified as reactive spots specific to SN-APS serum. Autoantibody for C9 was detected in 2/14 SN-APS patients with no known thrombotic predisposition, and in 1/12 SN-APS patients with a known thrombotic predisposition other than APS by WB using purified C9 treated with iodoacetamide. The reaction was not seen in control sera (0/4). This study suggests that some SN-APS pathologies relate to autoantibodies that react to specific C9 epitopes expressed under fixed conditions.

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  • The molecular mechanism of progesterone signaling to modulate cervical remodeling

    Grant number:24592488  2012.4 - 2015.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    KUWABARA Yoshimitsu, KATAYAMA Akira, NAKAI Akihito, KAWABATA Ikuno, TAKESHITA Toshiyuki

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    Grant amount:\5330000 ( Direct Cost: \4100000 、 Indirect Cost:\1230000 )

    Human uterine cervical fibroblast culture system was established from clinical specimens. Subsequently to the subculture in the medium containing beta-estradiol, expression dynamics of IL-6, IL-8, IL-1beta, PTGS2 and MMPs were assessed by real-time RT-PCR analysis.
    LPS (2.0μg/ml) stimulation induced a significant increase of transcript levels of all molecules, which were significantly suppressed by progesterone (P4)(1.0μM)treatment except for IL-6, IL-8. On the other hand, the effect of stimulation with lower concentration of LPS (0.2μg/ml) was suppressed by P4 treatment in all molecules. Furthermore, the suppression was pronounced by the pretreatment of P4 1 hour before LPS stimulation.
    Progesterone inhibit the expression of molecules related with preterm labor in a transcript level, and the timing of treatment is considered important in a clinical use to prevent preterm birth.

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  • スーパーオキサイド発生に伴う、胎盤組織における蛋白質動態のプロテオーム解析

    Grant number:16790976  2004

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    桑原 慶充

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    Grant amount:\2100000 ( Direct Cost: \2100000 )

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